PA289

PA289 is a first-in-class, seco-CBI based linker-payload developed by Iksuda Therapeutics for the creation of antibody-drug conjugates (ADCs). It features a unique protein alkylation (ProAlk) mechanism of action, which kills cancer cells by alkylating cytosolic proteins, leading to S-phase cell cycle arrest and apoptosis. The payload is designed as a glucuronide prodrug to enhance tolerability; it remains inactive until it is selectively cleaved by lysosomal glucuronidase, an enzyme often overexpressed in tumor cells. PA289 is conjugated to antibodies using Iksuda's stable, cysteine-specific PermaLink technology. Preclinical data indicate that PA289-based ADCs are highly potent, trigger immunogenic cell death, and are poor substrates for common drug efflux pumps (ABCB1 and ABCG2), allowing them to retain activity in models resistant to topoisomerase I inhibitor-based ADCs like trastuzumab deruxtecan.